Nitric Oxide and Endothelial Dysfunction

Abstract

Nitric oxide is a strong vasodilatory and anti-inflammatory signaling molecule that plays diverse roles in maintaining vascular homeostasis. Nitric oxide produced by endothelial cells is a critical regulator of this balance, such that endothelial dysfunction is defined as a reduced capacity for nitric oxide production and decreased nitric oxide sensitivity. This ultimately results in an imbalance in vascular homeostasis leading to a prothrombotic, proinflammatory, and less compliant blood vessel wall. Endothelial dysfunction is central in numerous pathophysiologic processes. This article reviews mechanisms governing nitric oxide production and downstream effects, highlighting the role of nitric oxide signaling in organ system pathologies.

Keywords: Endothelial dysfunction; Nitric oxide; Nitric oxide synthase.

Fig. 1.

eNOS regulation, coupling, and uncoupling. During coupled eNOS activity (blue side), in the presence of heme and tetrahydrobiopterin, electrons from NADPH are passed through a core of flavin adenine dinucleotide–flavin adenine mononucleotide in the reductase domain to the Heme prosthetic group on the oxygenase domain. Here, l-arginine and O₂ are consumed to create l-citrulline and NO. In the uncoupled state (red side), electrons are passed directly from the flavin adenine dinucleotide (FAD)–flavin adenine mononucleotide (FMN) core of the reductase domain to O₂, generating superoxide (O₂^•−), which can ultimately combine with locally produced NO to make peroxynitrite (ONOO⁻). Several of the effects of ONOO⁻ and NO are listed here, as well as factors contributing to both coupling and uncoupling of eNOS activity. These are explained in greater detail in the body of the text. VEGF, vascular endothelial growth factor.

Fig. 2.

The nitrate–nitrite–NO pathway. Increasingly, research is demonstrating that dietary nitrates and nitrites serve as an endogenous reservoir for noncanonically produced NO, particularly in hypoxic conditions when NOS may be less functional or predisposed to being uncoupled. A detailed explanation of this pathway can be found in the body of the text.

Fig. 3.

A brief overview of NO signaling in specific organ system pathophysiology. For more specific details and references, please refer to the body of the text.